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A rare group of inherited neuromuscular disorders characterized by clinical features of a congenital myopathy and centrally placed nuclei on muscle biopsy. The clinical picture and other histologic features varies according to gene involved and mode of inheritance.
ORPHA:595Classification level: Group of disorders
- Prevalence: Unknown
- Inheritance: Autosomal dominant or Autosomal recessive or X-linked recessive
- Age of onset: Childhood, Neonatal, Infancy, Adolescent, Adult
- ICD-10: G71.2
- OMIM: -
- UMLS: C0175709
- MeSH: -
- GARD: 101
- MedDRA: -
The exact prevalence and incidence of this group of diseases are unknown. For the X-linked form (XLMTM1) the incidence is estimated at 1/50,000 male birth.
These congenital myopathies are characterized by generalized muscle weakness that can range from mild to severe. Symptoms are often present at birth in the severe forms, but may first develop at any point during life, although onset in adulthood is unusual. In the severe forms the common symptoms include hypotonia, feeding difficulties and respiratory distress. Extraocular muscle involvement is also common in all forms. Other common signs and symptoms include delayed motor milestones, facial weakness and ptosis.
Centronuclear myopathies (CNMs) are genetically widely heterogeneous and have been attributed mainly to X-linked recessive mutations in MTM1 (Xq28), encoding myotubularin 1 (X-linked centronuclear myopathy), autosomal-dominant mutations in DNM2( 19p13.2), encoding dynamin-2, autosomal dominant or recessive mutations in BIN1 (2q14.3), encoding myc box-dependent-interacting protein 1, and autosomal-recessive mutations in RYR1 (19q13.2), encoding the skeletal muscle ryanodine receptor, and in TTN (2q31.2), encoding titin. More recently, there have also been reports on peculiar CNM phenotypes related to autosomal recessive mutations in SPEG (2q35), encoding the striated muscle preferentially expressed protein kinase, and mutations in CCDC78 (16p13.3), encoding the coiled-coil domain-containing protein-78.
Diagnosis is based on typical histological findings of central nuclei, hypotrophy and predominance of type I fibers.
The main differential diagnoses include other forms of congenital myopathies or other neuromuscular conditions with severe neonatal hypotonia.
In familial cases, prenatal diagnosis can be performed if the genetic background is known.
Genetic counseling should be offered to all patients and families in whom a diagnosis of CNM has been made.
Management and treatment
Management of CNM requires a multidisciplinary approach. No specific therapy exists yet but different therapeutic strategies are under investigation.
The prognosis of this group of disease is variable. Whereas the XLMTM1 is often fatal in infancy, dominant forms due to DNM2 mutations and some cases of the recessive BIN1-related form appear to be associated with a globally more favourable prognosis.
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